Acute postoperative pain and catastrophizing in unicompartmental knee arthroplasty: a prospective, observational, single-center, cohort study.

BACKGROUND AND OBJECTIVES: Pain catastrophizing is associated with acute pain after total knee arthroplasty. However, the association between pain catastrophizing and acute pain after unicompartmental knee arthroplasty (UKA) remains unclear. METHODS: We investigated the incidence of predicted high-pain and low-pain responders, based on a preoperative Pain Catastrophizing Scale score >20 or ≤20, respectively, and the acute postoperative pain course in both groups. Patients undergoing UKA were consecutively included in this prospective observational cohort study. Pain at rest and during walking (5 m walk test) was evaluated preoperatively, at 24 hours postoperatively, and on days 2-7 using a pain diary. RESULTS: 125 patients were included, with 101 completing the pain diary. The incidence of predicted high-pain responders was 31% (95% CI 23% to 40%). The incidence of moderate to severe pain during walking at 24 hours postoperatively was 69% (95% CI 52% to 83%) in predicted high-pain responders and 66% (95% CI 55% to 76%) in predicted low-pain responders; OR 1.3 (95% CI 0.5 to 3.1). The incidence of moderate to severe pain at rest 24 hours postoperatively was 49% (95% CI 32% to 65%) in predicted high-pain responders and 28% (95% CI 19% to 39%) in predicted low-pain responders; OR 2.6 (95% CI 1.1 to 6.1; p=0.03). Pain catastrophizing was not associated with increased cumulated pain during walking on days 2-7. CONCLUSIONS: The incidence of predicted high-pain responders in UKA was slightly lower than reported in total knee arthroplasty. Additionally, preoperative pain catastrophizing was not associated with acute postoperative pain during walking.

Population pharmacokinetic-pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.